JP2013047193A - Resveratrol and method for producing derivative thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a very practical and simple method for efficiently producing a resveratrol (RES) and a derivative thereof and a key intermediate for RES synthesis from an easily-available raw material.SOLUTION: The method includes: obtaining a key intermediate (3, 5-dimethoxy-4'-acetoxystilbene derivative) for RES synthesis by reacting 3,5-dimethoxyphenyl boronic acid derivative that can lead to RES synthesis and 4-acetoxystyrene derivative under an acid coupling condition in which a palladium catalyst is used; and then, producing RES and a derivative thereof through demethylating and deacetylating reactions.

Description

  The present invention relates to a method for producing a stilbene derivative by reacting a phenylboronic acid derivative and a styrene derivative by an oxidative coupling reaction using a palladium catalyst, and a 3,4 ′, 5-trimethyl derivative having the reaction as a key step. The present invention relates to a method for producing hydroxystilbene (resveratrol) and derivatives thereof.

で表される3, 4', 5-トリヒドロキシスチルベン（以下、「RES」と称することもある。)、であり、ブドウの皮やピーナッツなどに含まれているポリフェノールの一種である。RESはファイトアレキシン(植物の病原菌に対する防御機構の中で、植物体内で生合成される防御物質)として知られている。また、RESは抗酸化作用、抗炎症作用、抗ガン作用等、さまざまな生理活性を示す天然化合物であり、中でも前立腺ガンの予防効果があるとされている。 Resveratrol is formula 5:
[Formula 1]

3, 4 ′, 5-trihydroxystilbene (hereinafter sometimes referred to as “RES”), which is a kind of polyphenol contained in grape skins and peanuts. RES is known as phytoalexin (a defense substance that is biosynthesized in plants within the defense mechanism against plant pathogens). RES is a natural compound that exhibits various physiological activities such as antioxidative action, anti-inflammatory action, and anticancer action, and is said to have a prophylactic effect on prostate cancer.

As described above, since RES is expected to be applied in the food field and pharmaceuticals, many synthetic methods have been reported so far. Here are some examples.
MB Andrus et al. Used 3,5-dihydroxybenzoic acid as a starting material to protect phenolic hydroxyl groups with acetyl groups, conversion to acid chlorides, coupling with styrene derivatives using palladium catalysts, and deprotection by hydrolysis. RES is synthesized in four steps (Reaction Scheme 1).

［反応式1］
（M. B. Andrus et al. Tetrahedron Lett. 2003, 44, 4819-4822.）

[Reaction formula 1]
(MB Andrus et al. Tetrahedron Lett. 2003, 44, 4819-4822.)

  In addition, M. Guiso et al. Performed Heck-type coupling of 3,5-diacetoxystyrene and p-acetoxyiodobenzene using a palladium catalyst, and synthesized RES in two stages by hydrolysis (Scheme 2). .

［反応式2］
（M. Guiso et al. Tetrahedron Lett. 2002, 43, 597-598.）

[Reaction formula 2]
(M. Guiso et al. Tetrahedron Lett. 2002, 43, 597-598.)

  As is clear from the above example, the synthesis of the stilbene skeleton is the key in the RES synthesis method. As a method for synthesizing a stilbene skeleton, a synthesis method using a oxidative coupling reaction using a palladium catalyst from phenyl boronic acid and styrene by Y. C. Jung et al. Is known (Scheme 3).

［反応式3］
（Y. C. Jung et al. Org. Lett. 2003, 5, 2231-2234.）

[Reaction formula 3]
(YC Jung et al. Org. Lett. 2003, 5, 2231-2234.)

  However, Y. C. Jung et al. Have not clarified whether or not their methods can be applied to derivatives in which phenylboronic acid and phenyl groups in styrene are substituted with reactive functional groups. There is also no known attempt to use the method of Y. C. Jung et al. For RES synthesis.

  As described above, in the above prior art, the raw material is unstable, or the raw material is difficult to obtain, or has multiple steps and is not economical, and further, there are variations in various activities. There are various problems, such as not suitable for synthesizing derivatives that can be expected, and the supply of RES to the market is still only extraction methods from natural products, and RES products based on organic synthesis methods have not yet been industrialized.

M. B. Andrus et al. Tetrahedron Lett. 2003, 44, 4819-4822. M. Guiso et al. Tetrahedron Lett. 2002, 43, 597-598. Y. C. Jung et al. Org. Lett. 2003, 5, 2231-2234.

  An object of the present invention is to provide a method for producing RES and its derivatives, and a basic intermediate for the synthesis of RES, which have solved some of the above problems. That is, the object of the present invention is to start from readily available raw materials, and to use RES and its derivatives that are highly practical, as well as basic intermediates for RES synthesis (hereinafter, including basic intermediates, “RES derivatives”). It is also possible to provide a manufacturing method.

The present inventors paid attention to the method of YC Jung et al., And have intensively studied a RES synthesis method incorporating the oxidative coupling reaction. Depending on the type of the functional group, various side reactions such as elimination, modification and reaction inhibition of the functional group may occur under oxidative coupling reaction conditions. Therefore, the synthetic route leading to RES was carefully examined, and the synthetic route via intermediates with various functional groups was intensively studied.
As a result, surprisingly, a phenylboronic acid derivative having a specific functional group in a predetermined position and a styrene derivative having a specific functional group in a predetermined position, which can lead to RES synthesis, are subjected to oxidative coupling conditions using a palladium catalyst. It was discovered that the basic intermediate to RES synthesis can be efficiently obtained by reacting below, and the present invention has been achieved.

That is, the first aspect of the present invention is
A process for the preparation of 3,5-disubstituted stilbene derivatives comprising the formula 01:

［式中、X¹、X²およびR²は各々独立に、水素、炭素数１〜１２のアルキル基、炭素数７〜１２のアラルキル基、R³-O［式中、R³は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアルコキシ基、R⁴-C(=O)O［式中、R⁴は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシ基、シアノ基（CN）またはR⁵-C(=O)ONH［式中、R⁵は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシアミノ基を表す。但し、X¹およびX²が水素の場合を除く。］で表される3, 5-ジ置換フェニルボロン酸誘導体、及び式2：

[Wherein, X ¹ , X ² and R ² are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ³ —O [wherein R ³ is the number of carbon atoms] An alkyl group having 1 to 12 or an aralkyl group having 7 to 12 carbon atoms is represented. Alkoxy group represented by, in ^{R 4 -C (= O) O} [ wherein, R ⁴ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN) or R ⁵ —C (═O) ONH [wherein R ⁵ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group represented by the formula: However, except when X ¹ and X ² are hydrogen. And a 3,5-disubstituted phenylboronic acid derivative represented by the formula:

［式中、R¹は炭素数１〜１２のアルキル基、炭素数７〜１２のアラルキル基、R⁶-O［式中、R⁶は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアルコキシ基、R⁷-C(=O)O［式中、R⁷は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシ基、シアノ基（CN）またはR⁸-C(=O)ONH［式中、R⁸は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシアミノ基、アミノ基（NH₂）、ニトロ基（NO₂）、またはハロゲンを表す。］で表されるスチレン誘導体を、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式03：

[Wherein R ¹ is an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ⁶ —O [wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms or 7 to 12 carbon atoms] Represents an aralkyl group. Alkoxy group represented by, in ^{R 7 -C (= O) O} [ wherein, R ⁷ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁸ —C (═O) ONH [wherein R ⁸ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group, an amino group (NH ₂ ), a nitro group (NO ₂ ), or a halogen represented by ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound of formula 03:

［式中、X¹、X²、R¹およびR²は前記と同義である。］で表される3, 5-ジ置換スチルベン誘導体を得る工程を有して成る、3, 5-ジ置換スチルベン誘導体の製造方法を提供するものである。

[Wherein, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. And a process for obtaining a 3,5-disubstituted stilbene derivative represented by the formula:

The second aspect of the present invention corresponds to the case where the substituents X ¹ and X ² in the first aspect are methoxy groups (OMe). That is, a method for producing a 3,5-dimethoxystilbene derivative, which is a basic intermediate of RES synthesis and derivative synthesis thereof,

［式中、R²は水素、炭素数１〜１２のアルキル基、炭素数７〜１２のアラルキル基、R³-O［式中、R³は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアルコキシ基、R⁴-C(=O)O［式中、R⁴は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシ基、シアノ基（CN）またはR⁵-C(=O)ONH［式中、R⁵は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシアミノ基を表す。］で表されるフェニルボロン酸誘導体、及び式2：

[Wherein R ² is hydrogen, an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ³ —O [wherein R ³ is an alkyl group having 1 to 12 carbon atoms or 7 carbon atoms] Represents -12 aralkyl groups. Alkoxy group represented by, in ^{R 4 -C (= O) O} [ wherein, R ⁴ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN) or R ⁵ —C (═O) ONH [wherein R ⁵ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group represented by the formula: And a phenylboronic acid derivative represented by the formula 2:

［式中、R¹は炭素数１〜１２のアルキル基、炭素数７〜１２のアラルキル基、R⁶-O［式中、R⁶は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアルコキシ基、R⁷-C(=O)O［式中、R⁷は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシ基、シアノ基（CN）またはR⁸-C(=O)ONH［式中、R⁸は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシアミノ基、アミノ基（NH₂）、ニトロ基（NO₂）、またはハロゲンを表す。］で表されるスチレン誘導体を、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式3：

[Wherein R ¹ is an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ⁶ —O [wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms or 7 to 12 carbon atoms] Represents an aralkyl group. Alkoxy group represented by, in ^{R 7 -C (= O) O} [ wherein, R ⁷ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁸ —C (═O) ONH [wherein R ⁸ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group, an amino group (NH ₂ ), a nitro group (NO ₂ ), or a halogen represented by ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound represented by formula 3:

［式中、R¹およびR²は前記と同義である。］で表される3, 5-ジメトキシスチルベン誘導体を得る工程を有して成る、3, 5-ジメトキシスチルベン誘導体の製造方法を提供するものである。

[Wherein, R ¹ and R ² are as defined above. A process for obtaining a 3,5-dimethoxystilbene derivative represented by the formula:

The third aspect of the present invention is the production of a 3,5-dihydroxystilbene derivative comprising a second step in which the 3,5-dimethoxystilbene derivative 3 obtained in the second aspect is subsequently demethylated. It corresponds to the method.
That is, the third aspect of the present invention is a method for producing a 3,5-dihydroxystilbene derivative, which has the formula:

［式中、R²は前記と同義である。］で表されるフェニルボロン酸誘導体、及び式2：

[Wherein, R ² has the same meaning as described above. And a phenylboronic acid derivative represented by the formula 2:

［式中、R¹は前記と同義である。］で表されるスチレン誘導体を、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式3：

[Wherein, R ¹ has the same meaning as described above. ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound represented by formula 3:

［式中、R¹およびR²は前記と同義である。］で表される3, 5-ジメトキシスチルベン誘導体を得る第１工程、ならびに、得られた3, 5-ジメトキシスチルベン誘導体3の脱メチル化反応を行って、式4：

[Wherein, R ¹ and R ² are as defined above. And a demethylation reaction of the obtained 3,5-dimethoxystilbene derivative 3 to obtain a 3,5-dimethoxystilbene derivative represented by the formula:

［式中、R¹およびR²は前記と同義である。］で表される3, 5-ジヒドロキシスチルベン誘導体を得る第２工程を有して成る、3, 5-ジヒドロキシスチルベン誘導体の製造方法を提供するものである。

[Wherein, R ¹ and R ² are as defined above. And a method for producing a 3,5-dihydroxystilbene derivative, comprising a second step of obtaining a 3,5-dihydroxystilbene derivative represented by the formula:

The fourth aspect of the present invention is
A method for producing a 3,5-dihydroxy-4′-acetoxystilbene derivative, which is a basic intermediate of RES synthesis and its derivative synthesis, comprising the formula 1:

［式中、R²は前記と同義である。］で表されるフェニルボロン酸誘導体、及び式2-1：

[Wherein, R ² has the same meaning as described above. And a phenylboronic acid derivative represented by formula 2-1:

で表される4-アセトキシスチレンを、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式3-1：

4-acetoxystyrene represented by formula (3) is mixed in the presence of a palladium catalyst and a base to perform an oxidative coupling reaction, and then Formula 3-1:

［式中、R²は前記と同義である。］で表される3, 5-ジメトキシ-4'-アセトキシスチルベン誘導体を得る第１工程、ならびに、得られた3, 5-ジメトキシ-4'-アセトキシスチルベン誘導体の脱メチル化反応を行って、式4-1：

[Wherein, R ² has the same meaning as described above. The first step of obtaining a 3,5-dimethoxy-4′-acetoxystilbene derivative represented by formula (I) and the demethylation reaction of the obtained 3,5-dimethoxy-4′-acetoxystilbene derivative 4-1:

［式中、R²は前記と同義である。］で表される3, 5-ジヒドロキシ-4'-アセトキシスチルベン誘導体を得る第２工程を有して成る、3, 5-ヒドロキシ-4'-アセトキシスチルベン誘導体の製造方法を提供するものである。

[Wherein, R ² has the same meaning as described above. And a second step for obtaining a 3,5-dihydroxy-4′-acetoxystilbene derivative represented by the formula:

According to a fifth aspect of the present invention, the 3,5-dihydroxy-4′-acetoxystilbene derivative 4-1 obtained in the fourth aspect is converted into 3,4 ′, 5-trihydroxystilbene by subsequent deacetylation reaction. This corresponds to a method for producing 3,4 ′, 5-trihydroxystilbene (resveratrol) and its derivatives, which comprises the third step of obtaining (resveratrol) and its derivatives.
That is, the fifth aspect of the present invention is a process for producing 3,4 ′, 5-trihydroxystilbene (resveratrol) and derivatives thereof,

［式中、R²は前記と同義である。］で表されるフェニルボロン酸誘導体、及び式2-1：

[Wherein, R ² has the same meaning as described above. And a phenylboronic acid derivative represented by formula 2-1:

で表される4-アセトキシスチレンを、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式3-1：

4-acetoxystyrene represented by formula (3) is mixed in the presence of a palladium catalyst and a base to perform an oxidative coupling reaction, and then Formula 3-1:

［式中、R²は前記と同義である。］で表される3, 5-ジメトキシ-4'-アセトキシスチルベン誘導体を得る第１工程、得られた3, 5-ジメトキシ-4'-アセトキシスチルベン誘導体3-1の脱メチル化反応を行って、式4-1：

[Wherein, R ² has the same meaning as described above. A first step of obtaining a 3,5-dimethoxy-4'-acetoxystilbene derivative represented by formula (I), a demethylation reaction of the obtained 3,5-dimethoxy-4'-acetoxystilbene derivative 3-1; Formula 4-1:

［式中、R²は前記と同義である。］で表される3, 5-ジヒドロキシ-4'-アセトキシスチルベン誘導体を得る第２工程、ならびに、得られた3, 5-ジヒドロキシ-4'-アセトキシスチルベン誘導体4-1の脱アセチル化反応を行って、式5-1：

[Wherein, R ² has the same meaning as described above. And a deacetylation reaction of the obtained 3,5-dihydroxy-4'-acetoxystilbene derivative 4-1. Formula 5-1:

［式中、R²は前記と同義である。］で表される3, 4', 5-トリヒドロキシスチルベン誘導体を得る第３工程を有して成る、3, 4', 5-トリヒドロキシスチルベン（R²=H：レスベラトロール）およびその誘導体の製造方法を提供するものである。

[Wherein, R ² has the same meaning as described above. 3, 4 ′, 5-trihydroxystilbene derivative represented by the following formula: 3, 4 ′, 5-trihydroxystilbene (R ² = H: resveratrol) and derivatives thereof The manufacturing method of this is provided.

  According to the present invention, simple and highly practical RES can be efficiently produced starting from readily available raw materials based on a novel synthetic route. In addition, RES derivatives and basic intermediates leading to RES can be easily produced with high practicality.

Hereinafter, the present invention will be described in detail.
First, a novel synthetic reaction route (Step-1 (first step) to Step-3 (third step)) leading to the production of resveratrol (RES: Formula 5) of the present invention: Fifth implementation Embodiment) is represented by reaction formula 4:

［反応式４］
に示す。

[Reaction Formula 4]
Shown in

In the above formula, Step-1 comprises 3,5-dimethoxyphenylboronic acid (1-1) and 4-acetoxystyrene (2-1) by the oxidative coupling reaction in the presence of a palladium catalyst and a base. A first step for obtaining 3,5-dimethoxy-4′-acetoxystilbene (3-1),
In Step-2, 3,5-dimethoxy-4′-acetoxystilbene (3-1) obtained in the previous step is subjected to demethoxylation reaction to produce 3,5-dihydroxy-4′-acetoxystilbene which is a RES precursor. The second step of obtaining (4-1-1), and step 3 are carried out by deacetylation reaction of the precursor 3,5-dihydroxy-4′-acetoxystilbene (4-1-1) obtained in the previous step. The 3rd process of obtaining the target product resveratrol (RES: 5) is shown.

As can be seen from the above formula, the resveratrol (RES) production method of the present invention is a simple three-step synthesis method. Moreover, as will be specifically described in the following examples, the reaction yield of each step is good, and as an example, the reaction yield of each step is about 80% or more, The reaction yield can exceed 50%. Of course, it will be apparent to those skilled in the art that the overall process yield can be further improved by optimizing the reaction conditions of each process.
This three-step RES synthesis method has not yet been reported.
Both the starting materials 3,5-dimethoxyphenylboronic acid (1-1) and 4-acetoxystyrene (2-1) are commercially available.

  The oxidative coupling reaction performed in the presence of a palladium catalyst and a base, which is the first step among all the three steps, is the first embodiment of the present invention. That is, the first embodiment of the present invention is a method for producing a 3,5-disubstituted stilbene derivative, which comprises a compound of formula 01:

［式中、X¹、X²およびR²は各々独立に、水素、炭素数１〜１２のアルキル基、炭素数７〜１２のアラルキル基、R³-O［式中、R³は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアルコキシ基、R⁴-C(=O)O［式中、R⁴は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシ基、シアノ基（CN）またはR⁵-C(=O)ONH［式中、R⁵は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシアミノ基を表す。但し、X¹およびX²が水素の場合を除く。］で表される3, 5-ジ置換フェニルボロン酸誘導体、及び式2：

[Wherein, X ¹ , X ² and R ² are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ³ —O [wherein R ³ is the number of carbon atoms] An alkyl group having 1 to 12 or an aralkyl group having 7 to 12 carbon atoms is represented. Alkoxy group represented by, in ^{R 4 -C (= O) O} [ wherein, R ⁴ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN) or R ⁵ —C (═O) ONH [wherein R ⁵ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group represented by the formula: However, except when X ¹ and X ² are hydrogen. And a 3,5-disubstituted phenylboronic acid derivative represented by the formula:

［式中、R¹は炭素数１〜１２のアルキル基、炭素数７〜１２のアラルキル基、R⁶-O［式中、R⁶は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアルコキシ基、R⁷-C(=O)O［式中、R⁷は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシ基、シアノ基（CN）またはR⁸-C(=O)ONH［式中、R⁸は炭素数１〜１２のアルキル基もしくは炭素数７〜１２のアラルキル基を表す。］で表されるアシロキシアミノ基、アミノ基（NH₂）、ニトロ基（NO₂）、またはハロゲンを表す。］で表されるスチレン誘導体を、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式03：

[Wherein R ¹ is an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ⁶ —O [wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms or 7 to 12 carbon atoms] Represents an aralkyl group. Alkoxy group represented by, in ^{R 7 -C (= O) O} [ wherein, R ⁷ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁸ —C (═O) ONH [wherein R ⁸ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group, an amino group (NH ₂ ), a nitro group (NO ₂ ), or a halogen represented by ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound of formula 03:

［式中、X¹、X²、R¹およびR²は前記と同義である。］で表される3, 5-ジ置換スチルベン誘導体を得る工程を有して成る、3, 5-ジ置換スチルベン誘導体の製造方法を提供するものである。

[Wherein, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. And a process for obtaining a 3,5-disubstituted stilbene derivative represented by the formula:

  The above oxidative coupling reaction can be represented by reaction formula 5:

［反応式5］
で表される。
ここで、式03の化合物の内、X¹=X²=OMe（メトキシ基）, R¹=OAc（アセトキシ基）, R²=Hの場合が、RES前駆体である3,5-ジメトキシ-4'-アセトキシスチルベン（式3-1）：

[Reaction formula 5]
It is represented by
Here, among the compounds of Formula 03, the case where X ¹ = X ² = OMe (methoxy group), R ¹ = OAc (acetoxy group), R ² = H is the 3,5-dimethoxy- which is the RES precursor 4'-acetoxystilbene (Formula 3-1):

に相当する。

It corresponds to.

X ¹ , X ² and R ² in the 3,5-disubstituted stilbene derivative (01) which is one of the starting materials are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms. , R ³ —O [wherein R ³ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. Alkoxy group represented by, in ^{R 4 -C (= O) O} [ wherein, R ⁴ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁵ —C (═O) ONH [wherein R ⁵ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. . An acyloxyamino group represented by the formula: However, the case where X ¹ and X ² are hydrogen is excluded.

  Examples of the alkyl group having 1 to 12 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, n-hexyl, and 2-methyl. Pentyl, n-heptyl, 2-methylhexyl, n-octyl, 2-methylheptyl, 2-ethylhexyl, n-nonyl, 2-methyloctyl, n-decyl, 2-methylnonyl, n-undecyl, n-dodecyl, etc. Examples are chain or branched alkyl groups. Among these, Preferably it is a C1-C6, More preferably, it is a C1-C4 alkyl group, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, and sec-butyl.

  An aralkyl group having 7 to 12 carbon atoms refers to an alkyl group containing an aryl group. Examples thereof include aralkyl groups such as benzyl, phenylethyl, 2-phenylbutyl, 2-phenylhexyl and naphthylethyl. Of these, benzyl and phenylethyl are preferred.

Examples of the alkoxy group represented by R ³ —O include an alkoxy group corresponding to the alkyl group having 1 to 12 carbon atoms or the aralkyl group having 7 to 12 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, n-hexyloxy, 2-methylpentoxy, n-heptyloxy, 2-methylhexyloxy, n-octyloxy, 2-methylheptyloxy, 2-ethylhexyloxy, n-nonyloxy, 2-methyloctyloxy, n-decyloxy, n-undecyloxy, n-dodecyl Examples thereof include alkyloxy groups and aralkyloxy groups such as oxy, benzyloxy, phenylethyloxy, 2-phenylbutyloxy, 2-phenylhexyloxy and naphthylethyloxy. Among these, an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms is preferable, for example, a methoxy group.

Examples of the acyloxy group represented by R ⁴ —C (═O) O include an acyloxy group of a carboxylic acid corresponding to the alkyl group having 1 to 12 carbon atoms or the aralkyl group having 7 to 12 carbon atoms. Specifically, acetoxy, ethylacetoxy, n-propylacetoxy, i-propylacetoxy, n-butylacetoxy, sec-butylacetoxy, tert-butylacetoxy, n-pentylacetoxy, sec-pentylacetoxy, n-hexyl Acetoxy, 2-methylpentylacetoxy, n-heptylacetoxy, 2-methylhexylacetoxy, n-octylacetoxy, 2-methylheptylacetoxy, 2-ethylhexylacetoxy, n-nonylacetoxy, 2-methyloctylacetoxy, n-decylacetoxy , N-undecylacetoxy, n-dodecylacetoxy, benzylacetoxy, phenylethylacetoxy, 2-phenylbutylacetoxy, 2-phenylhexylacetoxy, naphthylethylacetoxy and the like It is done. Among these, Preferably, the acyloxy group of carboxylic acid corresponding to a C1-C6 alkyl group or a C7-C10 aralkyl group is mentioned, for example, acetoxy, ethylacetoxy, n-propylacetoxy, i- Acyloxy groups such as propylacetoxy, n-butylacetoxy, sec-butylacetoxy, tert-butylacetoxy, n-pentylacetoxy, sec-pentylacetoxy, n-hexylacetoxy, benzylacetoxy, phenylethylacetoxy, 2-phenylbutylacetoxy Can be mentioned.

Examples of the acyloxyamino group represented by R ⁵ —C (═O) ONH include an amino group substituted with an acyloxy group corresponding to the alkyl group having 1 to 12 carbon atoms or the aralkyl group having 7 to 12 carbon atoms. It is done. Specifically, acetoxyamino, ethylacetoxyamino, n-propylacetoxyamino, i-propylacetoxyamino, n-butylacetoxyamino, sec-butylacetoxyamino, tert-butylacetoxyamino, n-pentylacetoxyamino, sec- Pentylacetoxyamino, n-hexylacetoxyamino, 2-methylpentylacetoxyamino, n-heptylacetoxyamino, 2-methylhexylacetoxyamino, n-octylacetoxyamino, 2-methylheptylacetoxyamino, 2-ethylhexylacetoxyamino, n -Nonylacetoxyamino, 2-methyloctylacetoxyamino, n-decylacetoxyamino, n-undecylacetoxyamino, n-dodecylacetoxyamino, benzylacetoxyamino, phenylethylacetoxyamino, 2-pheny Butyl acetoxy amino, 2-phenyl-hexyl acetoxy amino, alkyl acetoxy amino group or an aralkyl acetoxy amino groups such as naphthyl ethyl acetoxy amino. Among these, Preferably, the acyloxyamino group of carboxylic acid corresponding to a C1-C6 alkyl group or a C7-C10 aralkyl group is mentioned, for example, acetoxyamino, ethylacetoxyamino, n-propyl Acetoxyamino, i-propylacetoxyamino, n-butylacetoxyamino, sec-butylacetoxyamino, tert-butylacetoxyamino, n-pentylacetoxyamino, sec-pentylacetoxyamino, n-hexylacetoxyamino, benzylacetoxyamino, phenyl Examples include acyloxyamino groups such as ethylacetoxyamino and 2-phenylbutylacetoxyamino.

The other starting material, 4-substituted styrene (formula 2), the 4-position substituent R ¹ is an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ⁶ —O [wherein , R ⁶ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. Alkoxy group represented by, in ^{R 7 -C (= O) O} [ wherein, R ⁷ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁸ —C (═O) ONH [wherein R ⁸ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group, an amino group (NH ₂ ), a nitro group (NO ₂ ), or a halogen represented by

  Examples of the alkyl group having 1 to 12 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, n-hexyl, and 2-methyl. Pentyl, n-heptyl, 2-methylhexyl, n-octyl, 2-methylheptyl, 2-ethylhexyl, n-nonyl, 2-methyloctyl, n-decyl, 2-methylnonyl, n-undecyl, n-dodecyl, etc. Examples are chain or branched alkyl groups. Among these, Preferably it is a C1-C6, More preferably, it is a C1-C4 alkyl group, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, and sec-butyl.

  An aralkyl group having 7 to 12 carbon atoms refers to an alkyl group containing an aryl group. Examples thereof include aralkyl groups such as benzyl, phenylethyl, 2-phenylbutyl, 2-phenylhexyl and naphthylethyl. Of these, benzyl and phenylethyl are preferred.

Examples of the alkoxy group represented by R ⁶ —O include an alkoxy group corresponding to the alkyl group having 1 to 12 carbon atoms or the aralkyl group having 7 to 12 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, n-hexyloxy, 2-methylpentoxy, n-heptyloxy, 2-methylhexyloxy, n-octyloxy, 2-methylheptyloxy, 2-ethylhexyloxy, n-nonyloxy, 2-methyloctyloxy, n-decyloxy, n-undecyloxy, n-dodecyl Examples thereof include alkyloxy groups and aralkyloxy groups such as oxy, benzyloxy, phenylethyloxy, 2-phenylbutyloxy, 2-phenylhexyloxy and naphthylethyloxy. Among these, an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms is preferable, for example, a methoxy group.

Examples of the acyloxy group represented by R ⁷ —C (═O) O include an acyloxy group of a carboxylic acid corresponding to the alkyl group having 1 to 12 carbon atoms or the aralkyl group having 7 to 12 carbon atoms. Specifically, acetoxy, ethylacetoxy, n-propylacetoxy, i-propylacetoxy, n-butylacetoxy, sec-butylacetoxy, tert-butylacetoxy, n-pentylacetoxy, sec-pentylacetoxy, n-hexyl Acetoxy, 2-methylpentylacetoxy, n-heptylacetoxy, 2-methylhexylacetoxy, n-octylacetoxy, 2-methylheptylacetoxy, 2-ethylhexylacetoxy, n-nonylacetoxy, 2-methyloctylacetoxy, n-decylacetoxy , N-undecylacetoxy, n-dodecylacetoxy, benzylacetoxy, phenylethylacetoxy, 2-phenylbutylacetoxy, 2-phenylhexylacetoxy, naphthylethylacetoxy and the like It is done. Among these, Preferably, the acyloxy group of carboxylic acid corresponding to a C1-C6 alkyl group or a C7-C10 aralkyl group is mentioned, for example, acetoxy, ethylacetoxy, n-propylacetoxy, i- Acyloxy groups such as propylacetoxy, n-butylacetoxy, sec-butylacetoxy, tert-butylacetoxy, n-pentylacetoxy, sec-pentylacetoxy, n-hexylacetoxy, benzylacetoxy, phenylethylacetoxy, 2-phenylbutylacetoxy Can be mentioned.

Examples of the acyloxyamino group represented by R ⁸ —C (═O) ONH include an amino group substituted with an acyloxy group corresponding to the alkyl group having 1 to 12 carbon atoms or the aralkyl group having 7 to 12 carbon atoms. It is done. Specifically, acetoxyamino, ethylacetoxyamino, n-propylacetoxyamino, i-propylacetoxyamino, n-butylacetoxyamino, sec-butylacetoxyamino, tert-butylacetoxyamino, n-pentylacetoxyamino, sec- Pentylacetoxyamino, n-hexylacetoxyamino, 2-methylpentylacetoxyamino, n-heptylacetoxyamino, 2-methylhexylacetoxyamino, n-octylacetoxyamino, 2-methylheptylacetoxyamino, 2-ethylhexylacetoxyamino, n -Nonylacetoxyamino, 2-methyloctylacetoxyamino, n-decylacetoxyamino, n-undecylacetoxyamino, n-dodecylacetoxyamino, benzylacetoxyamino, phenylethylacetoxyamino, 2-pheny Butyl acetoxy amino, 2-phenyl-hexyl acetoxy amino, alkyl acetoxy amino group or an aralkyl acetoxy amino groups such as naphthyl ethyl acetoxy amino. Among these, Preferably, the acyloxyamino group of carboxylic acid corresponding to a C1-C6 alkyl group or a C7-C10 aralkyl group is mentioned, for example, acetoxyamino, ethylacetoxyamino, n-propyl Acetoxyamino, i-propylacetoxyamino, n-butylacetoxyamino, sec-butylacetoxyamino, tert-butylacetoxyamino, n-pentylacetoxyamino, sec-pentylacetoxyamino, n-hexylacetoxyamino, benzylacetoxyamino, phenyl Examples include acyloxyamino groups such as ethylacetoxyamino and 2-phenylbutylacetoxyamino.
As the halogen, F or Cl is preferable.

The second embodiment of the present invention is the case where X ¹ = X ² = MeO (methoxy group) in the ^first embodiment,

［式中、R²は前記と同義である。］で表される3,5-ジメトキシフェニルボロン酸誘導体、及び式2：

[Wherein, R ² has the same meaning as described above. And a 3,5-dimethoxyphenylboronic acid derivative represented by the formula:

［式中、R¹は前記と同義である。］で表されるスチレン誘導体を、パラジウム触媒および塩基の存在下に混合して酸化的カップリング反応を行って、式3：

[Wherein, R ¹ has the same meaning as described above. ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound represented by formula 3:

［式中、R¹およびR²は前記と同義である。］で表される3, 5-ジメトキシスチルベン誘導体を得る工程を有して成る、3, 5-ジメトキシスチルベン誘導体の製造方法を提供するものである。

[Wherein, R ¹ and R ² are as defined above. A process for obtaining a 3,5-dimethoxystilbene derivative represented by the formula:

  The above oxidative coupling reaction can be represented by a reaction formula:

［反応式6］
で表される。
ここで、式3の化合物の内、R¹=アセトキシ基（OAc）でR²=Hの場合が、RES前駆体である3,5-ジメトキシ-4'-アセトキシスチルベン（式3-1）：

[Reaction formula 6]
It is represented by
Here, among the compounds of formula 3, when R ¹ = acetoxy group (OAc) and R ² = H, 3,5-dimethoxy-4′-acetoxystilbene (formula 3-1) is a RES precursor:

に相当する。

It corresponds to.

R ¹ in phenylboronic acid (formula 1) which is one of the starting materials has the same meaning as described above. Among these, R ¹ is particularly preferably hydrogen or a methoxy group (OMe). Preferred examples of the phenylboronic acid compound used in the present invention include 3,5-dimethoxyphenylboronic acid (formula 1-1):

および3,4,5-トリメトキシフェニルボロン酸（式1-2）：

And 3,4,5-trimethoxyphenylboronic acid (Formula 1-2):

が挙げられる。

Is mentioned.

The substituent R ^{1 at} the 4-position of the other starting material 4-substituted styrene (formula 2) is as defined above. Among them, R ¹ is particularly preferably an acetoxy group (OAc), a methoxy group (OMe), an amino group (NH ₂ ), a nitro group (NO ₂ ), fluorine (F) or chlorine (Cl). Examples of specific compounds are as follows.

Next, the oxidative coupling reaction using a palladium catalyst and a base will be described.
In this reaction, a phenylboronic acid derivative (formula 1) and 4-substituted styrene (formula 2) are dissolved in an appropriate solvent in a reaction vessel, and after adding and mixing a palladium compound and a base, oxygen or The reaction is performed by stirring for a predetermined time at a predetermined temperature in an air atmosphere.

The composition ratio of the raw materials is usually in the range of 0.5 to 8 mol, preferably 1 to 5 mol, particularly preferably 1.5 to 3 mol of the substituted phenylboronic acid derivative with respect to 1 mol of the 4-position substituted styrene derivative. , 2 moles. The reaction yield of the oxidative coupling reaction in the examples described later is expressed as the yield of the produced stilbene derivative with respect to the substituted styrene.
The concentration of the raw material (phenylboronic acid derivative + styrene derivative) in the reaction solvent is 0.1 to 50 wt%, preferably 1 to 30 wt%, more preferably 1 to 20 wt%, for example (numerical value of Example) wt%. It is.

Various palladium compounds can be used as the palladium catalyst, but preferably bisacetonitrile palladium chloride (II): (CH ₃ CN) ₂ PdCl ₂ , palladium chloride: PdCl ₂ , palladium acetate: Pd (OAc) ₂ and At least one palladium compound selected from the group consisting of allyl palladium (II) chloride dimer: [Pd (η ³ -C ₃ H ₅ Cl)] ₂ can be used. Of these palladium compounds, bisacetonitrile palladium chloride (II), palladium chloride and palladium acetate are particularly preferred in that the reaction yield of the oxidative coupling reaction is excellent.
The amount of the palladium catalyst is usually 0.1 to 50 mol%, preferably 1 to 30 mol%, more preferably 5 to 20 mol%, for example 10 mol%, based on 1 mol of 4-substituted styrene. The amount of the catalyst can be appropriately set depending on the reaction temperature, reaction time, etc., depending on the desired reaction yield. Against

Various base compounds can be used as the base and are not particularly limited. In consideration of the fact that the reaction is performed in an oxidative atmosphere, an inorganic base that is not easily oxidized is preferable. It should be noted that the strength of the base also affects the reaction. In particular, in the case of the present invention, since a phenylboronic acid derivative and a styrene derivative substituted with reactive functional groups are used as starting materials, side reactions such as elimination and modification of functional groups occur when the base strength is too strong. obtain. Preferable bases include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and sodium carbonate and potassium carbonate are particularly preferable.
Since the amount of the base is considered to act on the neutralization of the phenylboronic acid derivative, an amount approximately equimolar with the phenylboronic acid derivative used is usually used.

The reaction is usually carried out by mixing raw materials and catalyst components in a solvent. The reaction solvent is not particularly limited as long as it is an inert solvent which dissolves the raw material substrate and the catalyst component and keeps the raw material, the catalyst component and the product stable. Preferred solvents are generally non-protic polar solvents that do not have active hydrogen. Examples thereof include nitrogen-containing solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and acetonitrile, ketones such as acetone, methyl ethyl ketone and dioxane, and ether solvents. Of these, particularly preferred solvents are DMF and DMSO.
These solvents are preferably used after dehydration. A trace amount of water in the solvent inhibits the oxidative coupling reaction.

The oxidative coupling reaction is carried out in an oxygen or air atmosphere. Oxygen is necessary for reoxidation of the catalyst and is an essential component for improving the catalyst cycle (catalyst efficiency). In an actual reaction, raw materials, a catalyst, and a solvent are charged into a reaction vessel, and then oxygen substitution is performed. Thereafter, the reaction is performed while maintaining an oxygen or air atmosphere.
Since the reaction is in an oxygen atmosphere, it is always necessary to pay attention so that the ratio of vapor-phase organic vapor to oxygen deviates from the explosion limit.
The reaction temperature is usually 0 to 120 ° C, preferably 10 to 80 ° C, more preferably 20 to 60 ° C, for example 50 ° C.
The reaction time depends on the desired reaction yield, reaction temperature, amount of catalyst, substrate concentration, etc., but is usually 0.2 to 50 hours, preferably 0.5 to 48 hours, more preferably 1 to 30 hours, for example 3 ~ 24 hours.
After confirming the end point of the oxidative coupling reaction by gas chromatography and liquid (or thin layer) chromatography, etc., lower the reaction temperature to near room temperature, extract the product with an extraction solvent such as ethyl acetate, and wash several times with saturated saline. Thereafter, the extract is dried with a desiccant such as anhydrous sodium sulfate. After filtering the desiccant, the solvent is distilled off under reduced pressure to obtain a crude product. The crude product can be purified by a conventional method such as recrystallization or column chromatography to obtain the RES backbone intermediate of the product. In Examples described later, the product was confirmed by IR-spectrum (FT / IR-460 Plus manufactured by JASCO), ¹ H-NMR and ¹³ C-NMR (JMTC-400 / 54 / manufactured by JEOL). SS), MS (MALDI-TOF mass spectrometer) and melting point measurement (BUCHI Melting Point B-545).

  In an embodiment corresponding to the third to fifth aspects of the present invention, a demethylation reaction is performed as the second step. That is, in the third embodiment, the 3,5-dimethoxystilbene derivative 3 obtained by the oxidative coupling reaction in the first step is converted into the reaction formula 7 in the second step:

［反応式7］
で表される脱メチル化反応を行って、3, 5-ジヒドロキシスチルベン誘導体4を得る工程を有して成る製造方法である。
第４および第５の実施態様は、第１工程の酸化的カップリング反応で得られた3, 5-ジメトキシ-4'-アセトキシスチルベン誘導体3-1を第２工程の反応式8：

[Reaction formula 7]
Is a production method comprising a step of obtaining 3,5-dihydroxystilbene derivative 4 by performing a demethylation reaction represented by the following formula.
In the fourth and fifth embodiments, the 3,5-dimethoxy-4′-acetoxystilbene derivative 3-1 obtained by the oxidative coupling reaction in the first step is converted into the reaction formula 8 in the second step:

［反応式8］
で表される脱メチル化反応を行って、式4-1で表される3, 5-ジヒドロキシ-4'-アセトキシスチルベン誘導体を得る工程を有して成る製造方法である。

[Reaction Formula 8]
And a 3,5-dihydroxy-4′-acetoxystilbene derivative represented by formula 4-1 is obtained by performing a demethylation reaction represented by formula (4-1).

  The type of demethylation reaction is not particularly limited. For example, a reaction such as demethylation using aluminum chloride and ethanethiol in a methylene chloride solvent can be used. Among them, a demethylation reaction preferably performed using boron trichloride and tetra-n-butylammonium iodide may be used. The amount of tetra-n-butylammonium iodide used is 1 to 6 mol, preferably 1 to 4 mol, for example, about 3 mol with respect to 1 mol of 3,5-dimethoxystilbene derivative 3 or 3-1 as a demethylation raw material. is there. The amount of boron trichloride is about the equivalent of tetra-n-butylammonium iodide.

  The demethylation reaction is usually performed in a dehydrated solvent at a liquid nitrogen temperature of −78 ° C. to 50 ° C., preferably −78 ° C. to 30 ° C., for example, −78 ° C. to room temperature, and stirred in a nitrogen gas atmosphere. And do it. As the solvent, aprotic polar solvents such as dichloromethane, 1,2-dichloroethane and chloroform are usually used. The order of mixing the reaction raw materials is not particularly limited, but it is preferable that a methoxy-substituted stilbene derivative and tetra-n-butylammonium iodide are dissolved in a solvent, and then a boron trichloride solution dissolved in the solvent is added dropwise. At this time, the dropwise addition of the boron trichloride solution is preferably performed at a low temperature, for example, −78 ° C. This is to avoid sudden reaction start. After the addition of boron trichloride, the internal temperature is gradually raised to 10 ° C. to 50 ° C., for example, room temperature with stirring, and the reaction is continued for a predetermined time with further stirring. The reaction time is usually 0.5 to 24 hours, preferably 1 to 10 hours, for example 2 hours.

The reaction is completed by confirming the disappearance of the raw material by, for example, a thin layer or column chromatography or gas chromatography. After completion of the reaction, an alkali such as an aqueous sodium hydrogen carbonate solution is added to stop the reaction, and boron is removed. Thereafter, post-treatment and purification are carried out in the usual manner according to the procedure described in the section of the oxidative coupling reaction to obtain a demethylated product. Confirmation of the obtained product was carried out in the same manner as described in the section of oxidative coupling reaction, IR-spectrum (FT / IR-460 Plus manufactured by JASCO), ¹ H-NMR and ¹³ C-NMR (Japan JMTC-400 / 54 / SS manufactured by Denshi, MS (MALDI-TOF mass spectrometer) and melting point measurement (BUCHI Melting Point B-545).

  In an embodiment corresponding to the fifth aspect of the present invention, a deacetylation reaction is performed as the third step. Specifically, the reaction formula shows that the 3,5-dihydroxystilbene derivative 4-1 obtained by the demethylation reaction in the second step is deacetylated to produce 3,4 ′, 5-trihydroxystilbene. Scheme 9 to obtain derivative 5-1:

［反応式9］
で表される第３工程である。式5-1において、R₂=Hの場合がレスベラトロール（RES: 5）：

[Reaction formula 9]
It is the 3rd process represented by these. In formula 5-1, when R ₂ = H, resveratrol (RES: 5):

に相当する。
本発明において、脱アセチル化反応の方式は特に限定するものではなく、アルカリ水溶液による通常の脱アセチル化反応（即ち、アルカリ加水分解反応）を用いてよい。アルカリとしては、通常、水酸化ナトリウムおよび水酸化カリウム等の無機アルカリを用いてよい。アルカリ水溶液の濃度は、通常、5〜80wt%、好ましくは20〜60wt%、例えば50wt%であってよい。反応は通常、原料のアセトキシスチルベン誘導体を溶媒、例えば、テトラヒドロフラン（THF）やジメチルエーテル（DME）、ジオキサン等のエーテル系溶媒に溶解し、アルカリ水溶液と混合・撹拌して行う。反応温度は通常、0〜100℃、好ましくは20〜80℃、例えば70℃であり、反応時間は通常、0.5〜24時間、好ましくは1〜10時間、例えば2時間である。

It corresponds to.
In the present invention, the method of the deacetylation reaction is not particularly limited, and a normal deacetylation reaction (that is, an alkali hydrolysis reaction) using an aqueous alkali solution may be used. In general, inorganic alkalis such as sodium hydroxide and potassium hydroxide may be used as the alkali. The concentration of the alkaline aqueous solution may be usually 5 to 80 wt%, preferably 20 to 60 wt%, for example 50 wt%. The reaction is usually carried out by dissolving the raw material acetoxystilbene derivative in a solvent, for example, an ether solvent such as tetrahydrofuran (THF), dimethyl ether (DME), or dioxane, and mixing and stirring with an aqueous alkali solution. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 80 ° C., for example 70 ° C., and the reaction time is usually 0.5 to 24 hours, preferably 1 to 10 hours, for example 2 hours.

The deacetylation reaction is completed by confirming the disappearance of the raw material by, for example, a thin layer or column chromatography or gas chromatography. After completion of the reaction, the alkali used is neutralized by adding an acid such as an aqueous hydrochloric acid solution to stop the reaction. Then, after performing post-treatment such as solvent extraction and water washing as usual according to the procedure described in the section of oxidative coupling reaction, purification by column chromatography, crystallization, etc. is performed to obtain a demethylated product. . Confirmation of the obtained product was carried out in the same manner as described in the section of oxidative coupling reaction, IR-spectrum (FT / IR-460 Plus manufactured by JASCO), ¹ H-NMR and ¹³ C-NMR (Japan JMTC-400 / 54 / SS manufactured by Electronics), MS (MALDI-TOF mass spectrometer), melting point measurement (BUCHI Melting Point B-545) and the like.

  As is well known, resveratrol (RES: Formula 5) obtained by the production method of the present invention has various physiological (pharmacological) activities. On the other hand, RES derivatives (including RES precursors and RES intermediates, and derivatives thereof) obtained by the production method of the present invention also exhibit various physiological (pharmacological) activities due to their common structural features. Is expected. RES (5) and typical derivatives thereof obtained by the production method of the present invention are listed below.

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto.
The 3,5-disubstituted phenylboronic acid derivatives and 4-substituted styrene derivatives used as starting materials in the following examples were either commercially available products (manufactured by Tokyo Chemical Industry Co., Ltd.) or were used after purification.

Example 1
[Synthesis of 4'-acetoxy-3,5-dimethoxystilbene (3-1)]

［反応式10］

[Reaction formula 10]

In a 25 ml eggplant type flask, p-acetoxystyrene (2-1: 41 mg; 0.25 mmol) was dissolved in anhydrous dimethylformamide, 3,5-dimethoxyphenylboronic acid (1-1: 91 mg; 0.5 mmol), carbonic acid Sodium (53 mg; 0.5 mmol) and bisacetonitrile palladium chloride (II) ((CH ₃ CN) ₂ PdCl ₂ : 6.5 mg; 0.025 mmol) were added. The mixture was degassed with oxygen and stirred at 50 ° C. for 3 hours in an oxygen gas atmosphere. After cooling to room temperature, ethyl acetate (20 ml) was added to quench the reaction and the reaction product was extracted, washed 3 times with saturated brine (10 ml), and dried over anhydrous sodium sulfate. After filtering the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (step elution: eluent of 10% to 20% AcOEt in hexane). (62.2 g; yield based on p-acetoxystyrene = 84%) was obtained. From the analytical data of the obtained product (below), the production of the target compound 3-1 was confirmed.

Rf = 0.3 (silica gel thin layer chromatography; developing solvent: hexane: AcOEt = 3: 1)
¹ H-NMR (CDCl ₃ ) δ: 7.50 (d, 2H, J = 8.6 Hz, H-2 ', H-6'), 7.08 (d, 2H, J = 8.6Hz, H-3 ', H- 5 '), 7.06 (d, 1H, J = 15 Hz, H-β), 6.98 (d, 1H, J = 15 Hz, H-α), 6.66 (d, 2H, J = 2.2 Hz, H-2 , H-6), 6.40 (t, 1H, J = 2.2Hz, H-4), 3.83 (s, 6H, OMe), 2.31 (s, 3H, OAc).
¹³ C-NMR (CDCl ₃ ) δ: 169.4 (C = O), 161.0, 150.1, 139.2, 134.9, 128.9, 128.2, 127.5, 121.8, 104.6, 100.1, 55.4 (OAc), 21.1 (OMe).

Example 2
[Synthesis of 4'-acetoxy-3,5-didihydroxystilbene (4-1-1)]

［反応式11］

[Reaction formula 11]

In a 25 ml eggplant-shaped flask, 3,5-dimethoxy-4'-acetoxystilbene (3-1) (78 mg 0.26 mmol) was dissolved in anhydrous dichloromethane (1.7 ml), and n-tetrabutylammonium iodide (0.24 g; 0.65 mmol) was added. After substituting with N ₂ gas, 1M BCl ₃ (in CH ₂ Cl ₂ ) (0.7 ml; 0.7 mmol) was added dropwise at −78 ° C., stirred for 5 minutes, and then allowed to react at room temperature for 2 hours. Thereafter, the reaction was stopped by adding a saturated aqueous sodium hydrogen carbonate solution (30 ml), followed by extraction three times with ethyl acetate (30 ml), washing with water and saturated brine, and drying over anhydrous sodium sulfate. After the desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (step elution method: CHCl ₃ solvent containing 1% to 5% MeOH) to give a RES precursor 4- 1-1 (51.9 mg; Yield = 73%) was obtained. From the analytical data of the obtained product (below), the production of the target compound 4-1-1 was confirmed.

Rf = 0.5 (CHCl ₃ : MeOH = 9: 1)
¹ H-NMR (acetone solution) δ: 8.25 (s, 2H, OH), 7.59 (d, 2H, J = 8.5Hz, H-2 ', H-6'), 7.03-7.11 (m, 4H, H -α, H-β, H-3 ', H-5'), 6.58 (d, 2H, J = 2.1 Hz, H-2, H-6), 6.31 (t, 1H, J = 2.1Hz, H -4), 2.25 (s, 3H, OAc).
¹³ C-NMR (acetone solution) δ: 169.6 (C = O), 159.6, 151.3, 140.3, 135.9, 129.9, 128.2, 128.1, 122.8, 106.0, 103.2, 20.9 (OAc).

Example 3
[Synthesis of 3,4 ', 5-trihydroxystilbene (resveratrol: RES: 5)]

［反応式12］

[Reaction formula 12]

  In a 25 ml eggplant-shaped flask, 3,5-dihydroxy-4'-acetoxystilbene (4-1-1) (68 mg; 0.25 mmol) was dissolved in THF, 50% aqueous sodium hydroxide solution (2 ml) was added dropwise and heated. The mixture was stirred for 2 hours under reflux. Then, 2M HCl was added until pH = 3, extracted three times with ethyl acetate (20 ml), washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (stepwise elution method: hexane eluent containing 20% to 35% AcOEt), and RES 5 (41.5 mg, yield = 73%) From the analytical data of the obtained product (below), the production of the target compound: RES 5 was confirmed.

Rf = 0.38 (Hexane: AcOEt = 1: 1)
¹ H-NMR (Acetone) δ: 8.56 (s, 1H, OH), 8.28 (s, 2H, OH), 7.40 (d, 2H, J = 8.5 Hz, H-2 ', H-6'), 7.01 (d, 1H, J = 16 Hz, H-β), 6.87 (d, 1H, J = 16 Hz, H-α), 6.83 (d, 2H, J = 8.8 Hz, H-3 ', H-5 '), 6.53 (d, 2H, J = 2.2 Hz, H-2, H-6), 6.25 (s, 1H, H-4) ⁽¹ .
¹³ C-NMR (Acetone) δ: 159.6, 158.1, 140.8, 129.9, 129.1, 128.7, 126.8, 116.4, 105.6, 102.6 ⁽¹ .

Examples 4-12
Under the same conditions as in Example 1, except that the kind of palladium compound, the kind of base and the kind of solvent were changed, an oxidative coupling reaction was carried out according to Example 1, and the reaction solution was treated and treated in the same manner. Was purified. The obtained results are shown in Table 1.

［反応式13］

[Reaction formula 13]

  Example 13

［反応式14］

[Reaction formula 14]

  An oxidative coupling reaction was carried out according to Example 1 except that the types of phenylboronic acid derivative: 2 and 4-substituted styrene derivative: 1 were changed. Post-treatment and purification were performed according to Example 1 to obtain various dimethoxystilbene derivatives (RES derivatives: 3). The obtained results are shown in Table 2.

The analysis results of the obtained RES derivative are shown below:
[Entry No.1] 4'-Fluoro-3, 5-dimethoxystilbene
Rf = 0.3 (Hexane: AcOEt = 9: 1)
¹ H-NMR (CDCl ₃ ) δ: 7.45-7.49 (m, 2H, H-2, H-6), 7.02-7.07 (m, 3H, H-β, H-3, H-5), 6.94 ( d, 1H, J = 16 Hz, H-α), 6.65 (d, 2H, J = 16 Hz, H-2, H-6), 6.40 (s, 1H, H-4), 3.83 (s, 6H , OMe).
¹³ C-NMR (CDCl ₃ ) δ: 160.9, 139.1, 128.4, 128.1, 128.0, 127.9, 115.7, 115.5, 104.5, 99.9, 55.3 (OMe).

[Entry No.2] 4'-Chloro-3, 5-dimethoxystilbene
Rf = 0.25 (Hexane: AcOEt = 9: 1)
¹ H-NMR (CDCl ₃ ) δ: 7.43 (d, 2H, J = 8.4 Hz, H-2 ', H-6'), 7.32 (d, 2H, J = 8.4 Hz, H-3 ', H- 5 '), 7.01 (d, 2H, J = 1.7 Hz, H-α, H-β), 6.66 (d, 2H, J = 2.2 Hz, H-2, H-6), 6.04 (t, 1H, J = 2.2 Hz, H-4), 3.83 (s, 6H, OMe).
¹³ C-NMR (CDCl ₃ ) δ: 160.9, 138.9, 135.6, 133.3, 129.2, 128.8, 127.8, 127.7, 104.6, 100.1, 55.4 (OMe).

[Entry No.3] 4'-Nitro-3, 5-dimethoxystilbene
Rf = 0.38 (Hexane: AcOEt = 3: 1)
¹ H-NMR (CDCl ₃ ) δ: 8.22 (d, 2H, J = 8.8 Hz, H-3 ', H-5'), 7.63 (d, 2H, J = 8.8Hz, H-2 ', H- 6 '), 7.20 (d, 1H, J = 16 Hz, H-β), 7.11 (d, 1H, J = 16 Hz, H-α), 6.7 (d, 2H, J = 2.0 Hz, H-2 , H-6), 6.46 (t, 1H, J = 2.0Hz, H-4), 3.85 (s, 6H, OMe).
¹³ C-NMR (CDCl ₃ ) δ: 161.0, 146.7, 143.6, 138.0, 133.2, 126.9, 126.7, 124.1, 105.0, 100.9, 55.4 (OMe).

[Entry No.4] 4'-Amino-3, 5-dimethoxystilbene
Rf = 0.32 (Hexane: AcOEt = 2: 1)
¹ H-NMR (CDCl ₃ ) δ: 7.33 (d, 2H, J = 8.3 Hz, H-2 ', H-6'), 7.00 (d, 1H, J = 16 Hz, H-β), 6.85 ( d, 1H, J = 16 Hz, H-α), 6.67 (d, 2H, J = 8.3 Hz, H-3 ', H-5'), 6.63 (d, 2H, J = 1.7 Hz, H-2 , H-6), 6.36 (s, 1H, H-4), 3.82 (s, 6H, OMe), 3.76 (br, s, 2H, NH ₂ ).
¹³ C-NMR (CDCl ₃ ) δ: 160.9, 146.2, 139.9, 129.2, 127.8, 127.7, 124.9, 115.1, 104.1, 99.3, 55.3 (OMe).

[Entry No.5] 3, 4, 4 ', 5-tetramethoxystilbene
Rf = 0.4 (Hexane: AcOEt = 3: 1)
¹ H-NMR (CDCl ₃ ) δ: 7.45 (d, 2H, J = 8.8 Hz, H-2 ', H-6'), 6.89-7.00 (m, 4H, H-α, H-β, H- 3 ', H-5'), 6.72 (s, 2H, H-2, H-6), 3.92 (s, 6H, OMe), 3.87 (s, 3H, OMe), 3.84 (s, 3H, OMe) , 3.82 (s, 6H, OMe).
¹³ C-NMR (CDCl ₃ ) δ: 159.3, 153.4, 137.6, 133.4, 130.0, 127.7, 127.6, 126.5, 114.1, 103.3, 60.9 (OMe), 56.1 (OMe), 55.3 (OMe).

  Example 14

［反応式15］

[Reaction formula 15]

  A demethylation reaction was performed according to Example 2 except that the type of various dimethoxystilbene derivatives (RES derivative: 3) was changed. Post-treatment and purification were performed according to Example 2 to obtain various dihydroxystilbene derivatives (RES derivatives: 4). The obtained results are shown in Table 3.

The analysis results of the obtained RES derivative are shown below:
[No.1] 4'-Fluoro-3, 5-dihydroxystilbene (4-1-3)
Rf = 0.13 (Hexane: AcOEt = 3: 1)
¹ H-NMR (Acetone) δ: 8.28 (s, 2H, OH), 7.61-7.64 (m, 2H, H-2 ', H-6'), 7.02-7.15 (m, 4H, H-α, H -β, H-3 ', H-5'), 6.58 (d, 2H, J = 2.0 Hz, H-2, H-6), 6.32 (t, 1H, J = 2.0 Hz, H-4).
¹³ C-NMR (Acetone) δ: 159.6, 140.2, 134.8, 129.7, 129.7, 129.1, 129.0, 127.9, 116.3, 116.1, 105.9, 103.1.

[No.2] 4'-Chloro-3,5-dihydroxystilbene (4-1-4)
Rf = 0.14 (Hexane: AcOEt = 3: 1), Mp: 168.7 ° C
¹ H-NMR (Acetone) δ: 8.33 (s, 2H, OH), 7.60 (d, 2H, J = 8.3 Hz, H-2 ', H-6'), 7.39 (d, 2H, J = 8.5 Hz , H-α, H-β), 7.12 (s, 2H, H-3 ', H-5'), 6.60 (d, 2H, J = 2.0 Hz, H-2, H-6), 6.33 (s , 1H, H-4).
¹³ C-NMR (Acetone) δ: 159.6, 140.0, 137.2, 133.3, 130.6, 129.5, 128.8, 127.7, 106.0, 103.3.

By the production method of the present invention, resveratrol (RES), which relies exclusively on extraction from natural products, can be industrially efficiently produced by a simple organic synthetic method starting from readily available raw materials. . In addition, various RES derivatives and basic intermediates for RES synthesis can be easily and efficiently produced with high practicality.

Claims (12)

A process for the preparation of 3,5-disubstituted stilbene derivatives comprising the formula 01:

[Wherein, X ¹ , X ² and R ² are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ³ —O [wherein R ³ is the number of carbon atoms] An alkyl group having 1 to 12 or an aralkyl group having 7 to 12 carbon atoms is represented. Alkoxy group represented by, in ^{R 4 -C (= O) O} [ wherein, R ⁴ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN) or R ⁵ —C (═O) ONH [wherein R ⁵ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group represented by the formula: However, except when X ¹ and X ² are hydrogen. And a 3,5-disubstituted phenylboronic acid derivative represented by the formula:

[Wherein R ¹ is an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ⁶ —O [wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms or 7 to 12 carbon atoms] Represents an aralkyl group. Alkoxy group represented by, in ^{R 7 -C (= O) O} [ wherein, R ⁷ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁸ —C (═O) ONH [wherein R ⁸ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group, an amino group (NH ₂ ), a nitro group (NO ₂ ), or a halogen represented by ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound of formula 03:

[Wherein, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. A process for obtaining a 3,5-disubstituted stilbene derivative represented by the formula: A process for the preparation of 3,5-dimethoxystilbene derivatives, comprising formula 1:

[Wherein R ² is hydrogen, an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ³ —O [wherein R ³ is an alkyl group having 1 to 12 carbon atoms or 7 carbon atoms] Represents -12 aralkyl groups. Alkoxy group represented by, in ^{R 4 -C (= O) O} [ wherein, R ⁴ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN) or R ⁵ —C (═O) ONH [wherein R ⁵ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group represented by the formula: And a phenylboronic acid derivative represented by the formula 2:

[Wherein R ¹ is an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, R ⁶ —O [wherein R ⁶ is an alkyl group having 1 to 12 carbon atoms or 7 to 12 carbon atoms] Represents an aralkyl group. Alkoxy group represented by, in ^{R 7 -C (= O) O} [ wherein, R ⁷ represents an alkyl group or an aralkyl group having 7 to 12 carbon atoms having 1 to 12 carbon atoms. An acyloxy group, a cyano group (CN), or R ⁸ —C (═O) ONH [wherein R ⁸ represents an alkyl group having 1 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms. An acyloxyamino group, an amino group (NH ₂ ), a nitro group (NO ₂ ), or a halogen represented by ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound represented by formula 3:

[Wherein, R ¹ and R ² are as defined above. ] The manufacturing method of the 3, 5- dimethoxy stilbene derivative which comprises the process of obtaining the 3, 5- dimethoxy stilbene derivative represented by these. A process for the preparation of 3,5-dihydroxystilbene derivatives, comprising the formula 1:

[Wherein, R ² has the same meaning as described above. And a phenylboronic acid derivative represented by the formula 2:

[Wherein, R ¹ has the same meaning as described above. ] Is mixed in the presence of a palladium catalyst and a base to carry out an oxidative coupling reaction to obtain a compound represented by formula 3:

[Wherein, R ¹ and R ² are as defined above. And a demethylation reaction of the obtained 3,5-dimethoxystilbene derivative 3 to obtain a 3,5-dimethoxystilbene derivative represented by the formula:

[Wherein, R ¹ and R ² are as defined above. ] The manufacturing method of the 3, 5- dihydroxy stilbene derivative which has the 2nd process of obtaining the 3, 5- dihydroxy stilbene derivative represented by these. A process for the preparation of 3,5-dihydroxy-4'-acetoxystilbene derivatives comprising the formula 1:

[Wherein, R ² has the same meaning as described above. And a phenylboronic acid derivative represented by formula 2-1:

4-acetoxystyrene represented by formula (3) is mixed in the presence of a palladium catalyst and a base to perform an oxidative coupling reaction, and then Formula 3-1:

[Wherein, R ² has the same meaning as described above. The first step of obtaining a 3,5-dimethoxy-4′-acetoxystilbene derivative represented by formula (I) and the demethylation reaction of the obtained 3,5-dimethoxy-4′-acetoxystilbene derivative 4-1:

[Wherein, R ² has the same meaning as described above. And a second step of obtaining a 3,5-dihydroxy-4′-acetoxystilbene derivative represented by the formula: A process for the production of 3, 4 ', 5-trihydroxystilbene (resveratrol) and its derivatives, comprising formula 1:

[Wherein, R ² has the same meaning as described above. And a phenylboronic acid derivative represented by formula 2-1:

4-acetoxystyrene represented by formula (3) is mixed in the presence of a palladium catalyst and a base to perform an oxidative coupling reaction, and then Formula 3-1:

[Wherein, R ² has the same meaning as described above. A first step of obtaining a 3,5-dimethoxy-4'-acetoxystilbene derivative represented by formula (I), a demethylation reaction of the obtained 3,5-dimethoxy-4'-acetoxystilbene derivative 3-1; Formula 4-1:

[Wherein, R ² has the same meaning as described above. And a deacetylation reaction of the obtained 3,5-dihydroxy-4'-acetoxystilbene derivative 4-1. Formula 5-1:

[Wherein, R ² has the same meaning as described above. 3, 4 ′, 5-trihydroxystilbene derivative represented by the following formula: 3, 4 ′, 5-trihydroxystilbene (R ² = H: resveratrol) and derivatives thereof Manufacturing method. R ² is hydrogen or methoxy group (MeO), R ¹ is acetoxy group (OAc), methoxy group (OMe), amino group (NH ₂ ), nitro group (NO ₂ ), fluorine (F) or chlorine (Cl The manufacturing method according to any one of claims 1 to 3, wherein The production method according to claim 4 or 5, wherein R ² is hydrogen or a methoxy group (MeO).   The production method according to any one of claims 3 to 5 and 7, wherein the demethylation reaction is a reaction performed using boron trichloride and n-tetrabutylammonium iodide.   The production method according to claim 5, wherein the deacetylation reaction is a hydrolysis reaction with an alkaline aqueous solution. The palladium catalyst is at least one palladium compound selected from the group consisting of (CH ₃ CN) ₂ PdCl ₂ , PdCl ₂ , Pd (OAc) ₂ and [Pd (η ³ -C ₃ H ₅ Cl)] ₂ The manufacturing method of any one of Claims 1-9.   The production method according to any one of claims 1 to 10, wherein the base used in the oxidative coupling reaction with a palladium catalyst is sodium carbonate.   The production method according to any one of claims 1 to 11, wherein the palladium-catalyzed oxidative coupling reaction is carried out using dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) as a reaction solvent.